While there are many patents and publications available which relate to the transdermal administration of drugs, and the use of penetration enhancers, the applicant is unaware of any prior art which relates to the penetration enhancer composition of a monolithic transdermal device with adequate adhesive properties disclosed herein and to use such composition in the transdermal administration of drug(s).
The present invention relates to a novel composition based on enhancers combination, specifically fatty acids and fatty alcohols with different chain length in an adhesive matrix containing defined amount of chemicals as cellulose derivatives (ethylcellulose) to avoid cohesive failure. This formulation is suitable for transdermal administration of drug(s) alone or mixture thereof, and would provide therapeutically useful concentrations of drug for long periods of time, up to 7 (seven) days.
Using skin as the port for the drug entry offers unique potential, because transdermal delivery permits close control over drug absorption. For example, it avoids factors that can cause unpredictable absorption from the gastrointestinal tract, including: changes in acidity, motility, and food content. It also avoids initial metabolism of the drug by the liver. Thus, controlled drug entry through skin can achieve a high degree of control over blood concentrations of drug.
Transdermal delivery particularly benefits patients with chronic diseases. Many of such patients have difficulties following regimen requiring several daily doses of medications that repeatedly cause unpleasant symptoms. They find the same drugs much more acceptable when administered in transdermal systems that require, application infrequently, in some cases, only once or twice a week and that reduce adverse events.
Monolithic transdermal drug delivery systems involve incorporation of an active agent into the pressure sensitive adhesive formulation. The pressure sensitive adhesive must adhere effectively to the skin and then permit migration of the drug from the pressure sensitive adhesive through the skin and into the blood stream of the patient. Transdermal administration of drugs offers several therapeutic and compliance advantages over the more traditional routes of administration. A major drawback of this therapy however, is the limitation of the amount of drug that can be transported across the skin. This limitation is due to several factors. Since the skin is a protective barrier by nature, the rates of transport of most compounds through the skin is quite slow.
The rate of percutaneous absorption can be affected by the oil/water partition coefficient, the polarity of the drug and its degree of ionization, its solubility characteristic, molecular weight, volatility, concentration and the nature of the drug vehicle.
In order to overcome the barrier properties of the stratum corneum and facilitate the percutaneous absorption of the active agent, many compounds are described as penetration enhancers, such as, azone, glycol, pyrrolidone, fatty alcohol, fatty acid and ester thereof, etc., mentioned by M.o slashed.llgaard in "Pharmaceutical Skin Penetration Enhancement", Marcel Dekker, New York 1993, pages 229-242.
The behavior of an enhancer depends on the penetrant drug and the transdermal device design. That is, a given enhancer does not necessarily increase the absorption of all drugs, as it is quoted by Hori, Satoh and Maibach in "Percutaneous Absorption", Marcel Dekker, New York 1989, pages 197-211.
It is possible to excerpt from the scientific literature many examples in which two or more permeation enhancers in mixture have been shown to act synergically in percutaneous absorption enhancement.
A true synergically effect is achieved when the combination of permeation enhancers elicit a greater effect than the addition of the individual responses of each component used alone. However, for practical reasons the definition is expanded to comprise all examples for which two or more permeation enhancers in a mixture have worked well together in increasing the transport of drugs into and through the skin.
Cooper (1984) showed that the combination of propylene glycol and oleic acid increased the penetration of salicylic acid compared with each penetration enhancer alone. Aungst et al (1986) showed that the effects of permeation enhancer on absorption of naloxone in in vitro studies are vehicle dependent, showing that the combination of vehicles promotes the absorption better than one vehicle alone.
Green, Guy and Hadgraft (1988) reported that oleic and lauric acid can be employed to increase the permeability of human skin to a number of charged and uncharged molecules. The authors suggest that improved permeation is due to disruption of the stratum corneum structure.
Fatty acids are described as effective penetration enhancers for the transdermal delivery of several drugs. Golden et al. (1987) postulated that the likely enhancement mechanism of the fatty acids is mediated by the disruption of the stratum corneum lipid packed and hence decrease the diffusional resistance to permeants.
On the contrary Kadir et al. in "Pharmaceutical Skin Penetration Enhancement", Marcel Dekker, New York 1993, pages 215-227, assert that the mode of action of some enhancers is still unclear since, in most studies, no efforts have been made to distinguish between their direct effect on the skin barrier properties on the one hand, and their effects on the thermodynamic activity of the penetrating species in the vehicle on the other. It is quite likely that incorporating permeation enhancer in transdermal formulations will change the thermodynamic activity of the drug in the matrix, and thereby lead to a positive or negative "push" effect. In addition, some permeation enhancers may conceivable penetrate into the highly ordered intercellular lipid structure of the stratum corneum and reduce its resistance by increasing lipid acyl chain mobility, thus providing a "pull" effect.
It is now well accepted that the mechanism by which fatty acids and alcohols increase the skin permeability involves an interaction with the intercellular lipids in the stratum corneum. Alteration of the lipid bilayers has been assessed using differential scanning calorimetry (DSC) and fourier infrared spectroscopy (FTIR). These methods indicate that the enhancer system may cause a disruption of the ordered lamellar structure of the biolayers in the stratum corneum, leading to an increased fluidization of intercellular medium. As it is stated by M.o slashed.llgaard in "Pharmaceutical Skin Penetration Enhancement", Marcel Dekker, New York 1993, pages 229-242 it is likely that in a binary composition comprising oleic acid and propylene glycol, the propylene glycol enhances the oleic acid penetration, and oleic acid promotes the propylene glycol permeation. This mutual effect could thus result in a more rapid diffusion of the drug molecules across the skin.
The monolithic transdermal system, is a system incorporating a backing layer, a matrix layer and a release liner. The matrix layer is made of an adhesive polymer material in which the drug is dissolved or dispersed and the rate at which the drug is released from the device, is controlled by the diffusion within the polymer matrix following the Fick's law of diffusion.
This type of transdermal drug delivery system is exemplified by the development and marketing of nitroglycerin transdermal therapeutic system (Minitran by 3M) or estradiol (Climara by 3M) which have been approved by the FDA.
After a careful search looking for relevant documents to the present invention we become aware that the scientific information related to how the permeation enhancer(s) release from the transdermal systems to the skin, is scarce. Since only EP 0 279 982 describes a transdermal drug delivery system for administering contraceptives and codelivering of glycerol monooleate as permeation enhancer, to aid in drug delivery across the skin. In this patent application it is shown some results describing the release profile of glycerol monooleate.
EP 0 519 926 B1 discloses a transdermal delivery system, from which the release rate of the active agent is controlled by the dissociation of an inclusion complex of the active agent in a drug depot (cyclisized polysaccharide).
WO 93/25168 describes a transdermal drug delivery system which utilizes glycerine for moderating and controlling the delivery of drugs across biological membranes.
U.S. Pat. No. 5,466,465 discloses about a transdermal drug delivery system in which the drug granules are encapsulated within the material which controls the release over time of an active agent.
EPA 0 413 553 reveals a transdermal drug delivery in which drug delivery is biphasic. That is the drug is delivered at a therapeutically effective rate during an initial delivery phase, followed by a secondary phase in which no drug is delivered.
EPA 0 573 133 claims a transdermal device containing gestoden combined with one or more estrogens. The incorporation of penetration enhancer is also disclosed.
EPA 0 279 977 describes a transdermal device for administering progesterone and an estradiol ester alone or in combination, utilizing a polymer matrix which has the drug(s) with a penetration enhancer such as sucrose monococoate, glycerol monooleate, sucrose monolaurate, glycerol monolaurate, etc.
U.S. Pat. No. 5,023,084 claims a transdermal estrogen/progestin device comprising a polymeric layer made from polymer adhesive such as polyacrylic, silicone or other suitable polymer adhesives and n-decyl alcohol or capric acid as penetration enhancers.
WO 90/11 064 discloses a skin penetration enhancer composition for estrogen and progestin or a mixture thereof. The composition contains diethylene glycol monoethyl or monomethyl ether in addition to propylene glycol monolaurate, methyl laurate or the like.
U.S. Pat. No. 4,764,381 discloses a pharmaceutical preparation to obtain transdermal delivery of drug utilizing 2-ethyl-1, 3-hexanediol alone an/or in combination with oleic acid.
EP 0 551 349 claims the use of high boiling point solvents (in excess of 110.degree. C.) suitable for forming saturated or supersaturated solutions of the active agent in the transdermal device, such as propylene glycol, diethylene glycol, glycerol, fatty alcohols, fatty acids, esters, triglycerides, etc.
U.S. Pat. No. 4,863,970 discloses a binary penetration enhancement combination comprising oleic acid, oleyl alcohol or glycerol esters of oleic acid combined with lower alcohols.
U.S. Pat. No. 5,378,473 claims the use of ester of the formula [CH.sub.3 (CH.sub.2).sub.m COO].sub.n R, preferably propylene glycol monolaurate (PGML) and glycerol monooleate (GMO) as permeation enhancer in the transdermal administration of short or intermediate half-life benzodiazepines.
WO 95/01767 describes a monolithic matrix formulations for the transdermal administration of ketorolac tromethamine and molsidomine, also the inclusion of propylene glycol monolaurate (PGML) and propylene glycol (PG) as permeation enhancers is disclosed.
None of the above mentioned inventions or publications report a combination of fatty acids and/or fatty alcohols, such as oleic acid and lauric acid, oleic acid and lauryl alcohol, oleyl alcohol and lauric acid or oleyl alcohol and lauryl alcohol, in a transdermal monolithic device, with good adhesive properties and low irritation potential by means of the addition of a cohesive improver such as ethylcellulose and adequate tackifier resins, designed to administer active agent(s) or mixture thereof by the transdermal route.
The specific literature does not describe the addition of some "cohesion improver", as it is disclosed in the present invention. Typically, adding enhancers to PSA will plasticize the PSA and lower their shear strength. The reduction in shear resistance may result in adhesive residue on the skin, edge lifting of the patch during wear (cohesion failure), or loss of adhesion. The recovery of the tack and the adhesion can be made by addition of some tackifier agents as it is disclosed in the literature (Satas D., chapter 4: Tack, in Handbook of pressure sensitive adhesive technology, N. York 1989, pp. 38-60).
Chien in "Transdermal Controlled Systemic Medications", Marcel Dekker, New York 1987, pages 25-81, concludes that the efficacy of skin penetration enhancer for a specific active agent, is function of the type, concentration and, how the penetration enhancer release from the devices.
The prior art presented herein clearly proves that for some active agents, as shown in the present patent application, the penetration enhancer composition and the adequate controlled permeation rate across the skin can be achieved only by the careful investigation of multiple variables. Although prior art was useful for the theoretical approach.